Disease‐Duration–Specific Percentiles for Prospective Subtyping of Parkinson's Disease: A PPMI‐Based Study

Abstract

Abstract Background Parkinson's disease (PD) is clinically heterogeneous, with variable progression rates that complicate clinical trial design. The data‐driven diffuse malignant (DM), intermediate (IM), and mild‐motor predominant (MMP) subtyping model has prognostic value but lacks disease duration–specific thresholds for prospective use in disease‐modifying trials. Objective To define year‐specific percentile thresholds for key motor and non‐motor measures within the first 5 years after diagnosis to enable real‐time PD subtyping and assess progression patterns across subtypes. Methods We analyzed de‐identified PPMI data (downloaded April 22, 2026) from 1030 individuals with idiopathic PD. For each disease year, we computed percentiles for a composite motor score (MDS‐UPDRS II + III + PIGD) and non‐motor measures (MoCA, RBDSQ, SCOPA‐AUT). Thresholds were set at the 75th percentile for motor, RBDSQ, and SCOPA‐AUT, and the 25th percentile for MoCA, and applied annually to classify DM‐, IM‐, and MMP‐PD. Subtype stability (years 1–5) and progression were assessed using 25 predefined PPMI milestones. Kaplan–Meier and Cox regression models evaluated time to first milestone. Results Percentile thresholds worsened progressively over time, paralleling cohort‐level decline. DM‐PD prevalence ranged from 19.2–20.5% (IM 41.8–44.4%; MMP 35.1–38.8%). At baseline, clinical measures differed significantly across subtypes. Compared to MMP‐PD, DM‐PD (HR 3.03; 95% CI: 2.30–3.97) and IM‐PD (HR 1.48; 95% CI: 1.19–1.84) showed faster progression. Conclusions We establish disease duration–specific percentiles for prospective application of the DM/IM/MMP subtyping model, supporting patient stratification and enrichment in disease‐modifying trials.